title: Acute sensitivity of the oral mucosa to oncogenic K-ras.
abstract: Mouse models of cancer represent powerful tools for analysing the role of genetic alterations in carcinogenesis. Using a mouse model that allows tamoxifen-inducible somatic activation (by Cre-mediated recombination) of oncogenic K-ras(G12D) in a wide range of tissues, we observed hyperplasia of squamous epithelium located in moist or frequently abraded mucosa, with the most dramatic effects in the oral mucosa. This epithelium showed a sequence of squamous hyperplasia followed by squamous papilloma with dysplasia, in which some areas progressed to early invasive squamous cell carcinoma, within 14 days of widespread oncogenic K-ras activation. The marked proliferative response of the oral mucosa to K-ras(G12D) was most evident in the basal layers of the squamous epithelium of the outer lip with hair follicles and wet mucosal surface, with these cells staining positively for pAKT and cyclin D1, showing Ras/AKT pathway activation and increased proliferation with Ki-67 and EdU positivity. The stromal cells also showed gene activation by recombination and immunopositivity for pERK indicating K-Ras/ERK pathway activation, but without Ki-67 positivity or increase in stromal proliferation. The oral neoplasms showed changes in the expression pattern of cytokeratins (CK6 and CK13), similar to those observed in human oral tumours. Sporadic activation of the K-ras(G12D) allele (due to background spontaneous recombination in occasional cells) resulted in the development of benign oral squamous papillomas only showing a mild degree of dysplasia with no invasion. In summary, we show that oral mucosa is acutely sensitive to oncogenic K-ras, as widespread expression of activated K-ras in the murine oral mucosal squamous epithelium and underlying stroma can drive the oral squamous papilloma-carcinoma sequence.
authors.affiliation: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1HH, UK. lvdw@sanger.ac.uk
authors.forename: Louise
authors.initials: L
authors.lastname: van der Weyden
authors.forename: Maria P
authors.initials: MP
authors.lastname: Alcolea
authors.forename: Philip H
authors.initials: PH
authors.lastname: Jones
authors.forename: Alistair G
authors.initials: AG
authors.lastname: Rust
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Arends
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D011905:Genes, ras; D018859:Hair Follicle / Q000473:pathology; D006965:Hyperplasia / Q000139:chemically induced / Q000235:genetics; D051379:Mice; D009061:Mouth Mucosa / Q000187:drug effects / Q000473:pathology*; D009062:Mouth Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D012150:Polymorphism, Restriction Fragment Length; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012627:Sebaceous Glands / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D013629:Tamoxifen / Q000008:administration & dosage; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D013629:Tamoxifen; D051057:Proto-Oncogene Proteins c-akt